Hydrophobic Gating in Membrane Nanopores: Water at the Nanoscale
Lead Research Organisation:
University of Oxford
Department Name: Biochemistry
Abstract
The properties of water play a key role in biology, underlying all aspects of cellular structure and function. All cells are surrounded by lipidic membranes, in which there exist pore-like proteins which allow communication and exchange between the inside and outside of cells. Such nanoscale pores ('nanopores') are of great importance both in cell biophysics and as potential components of novel biosensors. Nanopores are filled with water. However, water behaves differently on the nanoscale, inside pores whose diameter is 10 millionths of diameter that of a human hair. In particular, nanopores can undergo spontaneous de-wetting if their lining is sufficiently hydrophobic (i.e. 'oily'). This provides a possible way in which to control the activity of nanopores if we can control their wetting/de-wetting.
We consequently need to understand and be able to model the physicochemical basis of wetting and de-wetting at a level of accuracy good enough for predictions to aid design of novel nanopores. This can be achieved by computer simulations - combining advanced algorithms and the power of modern supercomputers.
In this way, we will determine the behaviour of water in nanopores, understanding how they can be functionally 'opened and closed' by wetting and de-wetting, and how the imposition of a voltage difference across a nanopore-containing membrane can cause the nanopores to electrowet, thereby switching them from an inactive (closed) to an active (open) state.
This fundamental research will allow us to design controllable opening/closing of new nanopores for use in biosensors and other healthcare related applications.
We consequently need to understand and be able to model the physicochemical basis of wetting and de-wetting at a level of accuracy good enough for predictions to aid design of novel nanopores. This can be achieved by computer simulations - combining advanced algorithms and the power of modern supercomputers.
In this way, we will determine the behaviour of water in nanopores, understanding how they can be functionally 'opened and closed' by wetting and de-wetting, and how the imposition of a voltage difference across a nanopore-containing membrane can cause the nanopores to electrowet, thereby switching them from an inactive (closed) to an active (open) state.
This fundamental research will allow us to design controllable opening/closing of new nanopores for use in biosensors and other healthcare related applications.
Planned Impact
The impact of this work will be at the synthetic biology/nanotech interface, by enabling design of novel nanopores.
Thus, whilst this study is focussed on basic biological physics, this area of research underpins technologies for biosensing in relation to healthcare.
The long-term socio-economic benefits of the project will arise principally from advances in our exploitation of biomimetic nanopores in biosensors. There will also be impact in terms of improved methods for treating water in computational drug design; and modelling of water/biopolymer interactions for 'soft' hybrid materials. The principal beneficiaries will therefore be the biotech, healthcare and pharmaceutical industries and their stakeholders.
I will ensure maximum impact and exposure of the basic science discoveries via my ongoing engagement with relevant biotech and healthcare related industries. In this respect, I note that I have had recent collaborations with biotech (an iCASE student with ONT), and pharma (iCASE studentships with UCB), as well as emerging collaborations with Ipsen and with Novo Nordisk. I am a potential project supervisor for the joint EPSRC/BBSRC Synthetic Biology CDT, and also a director of the BBSRC-funded Interdisciplinary Bioscience DTP, which runs a highly successful Industry Day to foster contacts and collaborations with industrial partners. I will continue to showcase my group's work at these events.
Thus, whilst this study is focussed on basic biological physics, this area of research underpins technologies for biosensing in relation to healthcare.
The long-term socio-economic benefits of the project will arise principally from advances in our exploitation of biomimetic nanopores in biosensors. There will also be impact in terms of improved methods for treating water in computational drug design; and modelling of water/biopolymer interactions for 'soft' hybrid materials. The principal beneficiaries will therefore be the biotech, healthcare and pharmaceutical industries and their stakeholders.
I will ensure maximum impact and exposure of the basic science discoveries via my ongoing engagement with relevant biotech and healthcare related industries. In this respect, I note that I have had recent collaborations with biotech (an iCASE student with ONT), and pharma (iCASE studentships with UCB), as well as emerging collaborations with Ipsen and with Novo Nordisk. I am a potential project supervisor for the joint EPSRC/BBSRC Synthetic Biology CDT, and also a director of the BBSRC-funded Interdisciplinary Bioscience DTP, which runs a highly successful Industry Day to foster contacts and collaborations with industrial partners. I will continue to showcase my group's work at these events.
People |
ORCID iD |
Mark Sansom (Principal Investigator) | |
Anna Duncan (Researcher) |
Publications
Ansell TB
(2021)
Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.
in Journal of chemical theory and computation
Belessiotis-Richards A
(2020)
Coarse-Grained Simulations Suggest the Epsin N-Terminal Homology Domain Can Sense Membrane Curvature without Its Terminal Amphipathic Helix
in ACS Nano
Caffalette C
(2019)
A lipid gating mechanism for the channel-forming O antigen ABC transporter
in Nature Communications
Calvelo M
(2021)
Effect of Water Models on Transmembrane Self-Assembled Cyclic Peptide Nanotubes.
in ACS nano
Corey RA
(2022)
Cardiolipin, and not monolysocardiolipin, preferentially binds to the interface of complexes III and IV.
in Chemical science
Duncan AL
(2020)
Defining how multiple lipid species interact with inward rectifier potassium (Kir2) channels.
in Proceedings of the National Academy of Sciences of the United States of America
Flegler VJ
(2020)
The MscS-like channel YnaI has a gating mechanism based on flexible pore helices.
in Proceedings of the National Academy of Sciences of the United States of America
Gonzalez MA
(2021)
Influence of water models on water movement through AQP1.
in The Journal of chemical physics
Hammond K
(2021)
Switching Cytolytic Nanopores into Antimicrobial Fractal Ruptures by a Single Side Chain Mutation.
in ACS nano
Haynes T
(2018)
Electric-Field-Driven Translocation of ssDNA through Hydrophobic Nanopores.
in ACS nano
Description | 1. Water behaviour within a nanopore/channel hydrophobic gate has been characterised for different water models 2. We have three publications which will emerge in the next 12 months in this area demonstrating its application to model peptide nanopores and to ion channel proteins 3. We have published a major review in Chemical Reviews and three primary research publications (2 in ACS Nano and 1 in J Chem Phys). 4. Studies comparing MD and QM calculations on water in nanopores continue and we hope to publish the results later this year/early next. |
Exploitation Route | The methods we have developed can be applied in (i) analysis of biological ion channels and (ii) modelling and design of novel biomimetic nanopores, as has been demonstrated e.g. in our published collaborative studies. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | These finding formed the basis of collaborative discussions with colleagues from IBM research (UK), and with colleagues from Spain (Santiago & Madrid). The latter two collaborations progressed via papers which have now been published. The IBM collaboration has resulted in a partnership in graduate training (a DTC in computational discovery; https://www.ox.ac.uk/admissions/graduate/courses/dphil-computational-discovery) between Oxford and IBM, and is ongoing involving a number of colleagues from both physical and biological science departments in Oxford. |
First Year Of Impact | 2019 |
Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | Collaboration with Dr Rebeca Garcia-Fandino |
Organisation | University of Santiago de Compostela |
Country | Spain |
Sector | Academic/University |
PI Contribution | we provided advice on setup and analysis of water simulations for cyclic peptide nanopores |
Collaborator Contribution | a student visited my research group for 2 months to learn our simulation methods |
Impact | A paper has been published in ACS Nano |
Start Year | 2018 |
Description | Oxford/IBM |
Organisation | IBM |
Department | IBM Research in the UK |
Country | United Kingdom |
Sector | Private |
PI Contribution | We have established a major ongoing collaboration in biomolecular simulations and computational discovery between the Biochemistry Dept. and IBM Research UK. |
Collaborator Contribution | EPSRC iCASE studentships expertise in advanced computing methods for application to biomolecular simulations |
Impact | The major outcome to date is a joint DTC - see URL above |
Start Year | 2017 |
Description | Oxford/IBM |
Organisation | IBM |
Department | IBM Research in the UK |
Country | United Kingdom |
Sector | Private |
PI Contribution | We have established a major ongoing collaboration in biomolecular simulations and computational discovery between the Biochemistry Dept. and IBM Research UK. |
Collaborator Contribution | EPSRC iCASE studentships expertise in advanced computing methods for application to biomolecular simulations |
Impact | The major outcome to date is a joint DTC - see URL above |
Start Year | 2017 |
Description | collaboration with Dr.Chantal Valeriani |
Organisation | Complutense University of Madrid |
Country | Spain |
Sector | Academic/University |
PI Contribution | We have collaborated with Dr Valeriani and her team on the behaviour of different water models in simulations of aquaporins. We contributed expertise in water models and simulations of nanopores. This has resulted in a joint publication in J Chem Phys. |
Collaborator Contribution | Dr. Valeriani's post doc Dr Miguel Angel Gonzalez visited Oxford for a few weeks and worked alongside Dr Lynch (the EPSRC postdoc on this project). We have continued the collaboration online and a paper has been published in J Chem Phys. |
Impact | This has resulted in a joint publication in J Chem Phys. |
Start Year | 2018 |